Aspirin-exacerbated respiratory disease (AERD) is a subset of asthma, characterized by nasal polyposis and respiratory reactions to all medications that inhibit cyclooxygenase 1 (COX-1). These commonly used, non- steroidal anti-inflammatory drugs (NSAID) include aspirin. Desensitization using carefully controlled administration of aspirin and long-term aspirin treatment have been shown to be effective. In our diverse cohort of AERD patients, we identified patients who responded to aspirin treatment (responders), and those (more than one- third) who failed this standard treatment (non-responders). Our preliminary data: AERD has a strong type 2 (T2) pro-inflammatory state likely driven by high systemic levels of prostaglandin D2 (PGD2). Systemic PGD2 levels in plasma significantly decrease after endoscopic sinus surgery, as do clinical signs of aspirin sensitivity indicating that nasal polyp tissue is vital for promotion of T2 inflammation in AERD. In patients with undetectable levels of PGD2 in plasma (more than one-third of the study population), there are no detectable clinical reactions to aspirin after surgery. Non-responders to aspirin therapy in our AERD cohort had higher urinary PGD2 metabolite levels, higher baseline total serum immunoglobulin (Ig) E levels, and detectable serum IgE specific for Staphylococcus (S.) aureus enterotoxin A and/or B (SEA or SEB). We have also found that in non- responders, total serum IgE significantly increased after aspirin treatment for 4 weeks. Previous research: PGD2 activates T2-pro-inflammatory cells ? T-helper 2 allergic (Th2A) cells through chemoattractant receptor- homologous molecule expressed on Th2 cell (CRTH2) receptor, which binds PGD2. Unlike conventional Th2 cells, Th2A cells have high expression of hematopoietic prostaglandin D2 synthase (HPGDS), making PGD2 production by Th2A cells possible. Th2A cells are present in nasal polyps, where T2-inflammation is enhanced by allergic response against bacterial pathogens, especially S. aureus. Initial administration of aspirin to AERD patients leads to a multifold increase in systemic PGD2 levels. Continuous presence of both S. aureus antigen and high levels of PGD2 likely contributes to activation of Th2A cells. We propose to focus on nasal polyp tissue as the main driver of the T2 pro-inflammatory state. Central hypothesis: PGD2 and S. aureus synergistically activate Th2A cells in nasal polyps leading to aspirin treatment failure.
Aim 1. Determine activation of blood and nasal polyp Th2A cells in AERD patients according to clinical outcomes of aspirin treatment and in response to stimulation by S. aureus.
Aim 2. Determine whether stimulation of Th2A cells by S. aureus increases CRTH2 receptor and HPGDS expression. Results will inform the field by examining the role that Th2A cells play in aspirin treatment and how clinical outcomes could be modified by S. aureus-induced allergic response. Studies may offer insight into T2-inflammation of AERD and its alleviation by aspirin; improve selection of candidates for aspirin therapy; and lead to development of new therapies for patients who are refractory to current treatment.
Aspirin-exacerbated respiratory disease (AERD) is a subset of asthma, characterized by nasal polyposis and respiratory reactions to medications such as aspirin. While aspirin desensitization has been shown effective, more than one-third of patients fail to respond to this therapy. We propose to focus on nasal polyp tissue as the main driver of the T2 pro-inflammatory state that leads to aspirin treatment failure, thereby helping to elucidate the underlying pathophysiology; improve selection of candidates for aspirin therapy; and inform new treatment strategies.
